DISEASE/DRUG OF INTEREST: Naelgeria fowgleri/Miltefosine
MOTIVATION AND BACKGROUND: N. fowleri is a pathogenic amoeba that lives in warm bodies of freshwater such as ponds, lakes, and rivers in areas where these bodies of freshwater can high temperatures such as the southern tier states of the United States in the summertime. Infection occurs when the amoeba travels up a victim’s sinus cavity when water goes up their nose and attaches itself to the olfactory nerve, causing primary amoebic meningoencephalitis (PAM). This infection is very rare, there have only been 142 documented cases in the United States in the last 50 years, most of them occurring in southern states. This infection is very aggressive and has a very poor prognosis, only 2 of the 142 documented cases have not resulted in death. [1]
Figure1. Map highlighting the states where there have been reported cases of PAM In order for infection to occur water must travel up the victim’s nose which can happen when taking part in recreational activities such as swimming or diving and it can also occur if the patient is using the untreated water as a nasal irrigation solution. Once the amoeba attaches itself to the olfactory nerve it begins to consume nerve tissue and it enters the brain and continues to feed on nerve tissue causing necrosis of the brain. The infection causes flu-like symptoms to occur consisting of a stiff neck, a fever, and a headache and rapidly progressing to nausea, vomiting, delirium, seizures and coma. The disease progresses very rapidly with death occurring anywhere from 2 to 14 days after infection. Part of the reason this infection has such a poor prognosis is that many times victims don’t receive medical attention until symptoms of advanced necrosis begin to occur.[1]
Figure 2. This diagram demonstrates the life cycle of N. fowleri and how it causes infection when it travels into the olfactory nerve
When a patient is diagnosed with PAM the typical treatment is to administer a cocktail of anti-fungal and anti-protozoal drugs such as Amphotericin B intravenously in very high doses, however it is many times too late and most of the time the infection results in death.[2] Recently, however, the drug Miltefosine showed promising results as an amoebicidal drug and was listed by the CDC as an emergency treatment drug that can be ordered if any patient is diagnosed with PAM recommending a dose of a 50mg capsule taken 3 times a day.[1] In July of 2013 this drug was used with success to treat Kali Hardig, a 12 year old girl from Arkansas after she contracted the disease at a waterpark. Doctors administered this drug to Hardig intravenously after having lowered her body temperature to 93 degrees and Hardig made a recovery after 55 days.
TARGET INFORMATION: The target of this drug is still under investigation but it is strongly suggested that the target is a protein called nfa1 that is a key protein in the amoeba’s locomotion, adherence, and phagocytic abilities. This protein is found in the pseudopods of N. Fowleri and without it the amoeba would not be capable of moving by using its pseudopods and it is not capable of ingesting food by using food cups to ingest using phagocytosis. Naegleria gruberi is a non-pathogenic species of Naegleria and in a study done in 2006 the nfa1 protein was expressed in transinfected N. gruberi through the method of promoter modification. This resulted in the transinfected N. gruberi becoming pathogenic which supports the conclusion that the nfa1 gene is a key protein in making the N. fowleri amoeba pathogenic and capable of adhering to a human’s olfactory nerves.[3] The nfa1 protein is 13.1 kDa in size and if this protein is inhibited then the amoeba cannot spread as it usually does and will fail to be pathogenic.
DRUG INFORMATION: The drug miltefosine, also known under the name Impavido or Miltex, was originally derived artificially from a group of chemical compounds called alkylphosphocholines which are artificially synthesized phospholipid-like molecules. Miltefosine was originally being investigated as a potential cancer drug but it resulted in being toxic at the levels needed for effective treatment. It then was rediscovered as an anti-fungal and anti-protozoal drug and it is currently patented as a drug to treat leishmaniasis and atopic dermatitis. It is used in emergencies for PAM but since PAM is rare and has a very poor prognosis there have not been any clinical trials done of this drug.
Figure 3. A schematic representation of miltefosine, a non-polar phospholipid-like drug Formula: C21H46NO4P Molecular weight: 407.568002 g/mol CAS Number: 58066-85-6
The next step in the development of miltefosine or another similar drug alternative treatment for PAM would be to gain a better understanding of how miltefosine binds to the nfa1 protein inhibiting it and causing the spread of infection to stop. There have been several in vitro tests done using miltefosine on living N. fowleri to observe the drug’s beneficial effects and there have been tests done in vivo on mice to determine what concentrations are most effective which is great information but it would still be very beneficial to learn exactly how the drug binds to the protein in question. With this information, you can find other drugs, possibly drugs that are similar in structure to that of miltefosine, that make a better fit in the protein or do a better job of inhibiting the growth and spread of that particular protein. Having a better understanding of the binding of the drug to the protein will also help determine if there are certain conditions where binding is improved and the drug is more effective, maybe it binds more effectively when the patient has a lower body temperature such as when Hardig’s treatment proved effective in the summer of 2013. The fact that this disease occurs very rarely has a significant impact on how much research is done on the development of an effective drug such as miltefosine. Not only do the relatively few cases and fast progression of the disease make it very difficult to study the effects of a certain drug treatment but this also causes the funds for any research to be almost nonexistent. Despite these facts it is still important to find a drug such as miltefosine that can treat this disease if caught early since there are on average 2-3 cases every summer, all of which are most likely fatal.
REFERENCES: [1] CDC, Naegleria fowleri - Primary Amebic Meningoencephalitis (PAM). Centers for Disease Control and Prevention2014http://www.cdc.gov/parasites/naegleria/ [2] Jong-Hyun Kim, Suk-Yul Jung, Effect of Therapeutic Chemical Agents In Vitro and on Experimental Meningoencephalitis Due to Naegleria fowleri. Antimicrob Agents Chemother2008, 52, (11), 4010–4016. [3] Song KJ, Jeong SR, Naegleria fowleri: functional expression of the Nfa1 protein in transfected Naegleria gruberi by promoter modification. Exp Parasitol2006, 112, (2), 115-20.
Naelgeria fowgleri/Miltefosine
MOTIVATION AND BACKGROUND:
N. fowleri is a pathogenic amoeba that lives in warm bodies of freshwater such as ponds, lakes, and rivers in areas where these bodies of freshwater can high temperatures such as the southern tier states of the United States in the summertime. Infection occurs when the amoeba travels up a victim’s sinus cavity when water goes up their nose and attaches itself to the olfactory nerve, causing primary amoebic meningoencephalitis (PAM). This infection is very rare, there have only been 142 documented cases in the United States in the last 50 years, most of them occurring in southern states. This infection is very aggressive and has a very poor prognosis, only 2 of the 142 documented cases have not resulted in death. [1]
Figure1. Map highlighting the states where there have been reported cases of PAM
In order for infection to occur water must travel up the victim’s nose which can happen when taking part in recreational activities such as swimming or diving and it can also occur if the patient is using the untreated water as a nasal irrigation solution. Once the amoeba attaches itself to the olfactory nerve it begins to consume nerve tissue and it enters the brain and continues to feed on nerve tissue causing necrosis of the brain. The infection causes flu-like symptoms to occur consisting of a stiff neck, a fever, and a headache and rapidly progressing to nausea, vomiting, delirium, seizures and coma. The disease progresses very rapidly with death occurring anywhere from 2 to 14 days after infection. Part of the reason this infection has such a poor prognosis is that many times victims don’t receive medical attention until symptoms of advanced necrosis begin to occur.[1]
Figure 2. This diagram demonstrates the life cycle of N. fowleri and how it causes infection when it travels into the olfactory nerve
When a patient is diagnosed with PAM the typical treatment is to administer a cocktail of anti-fungal and anti-protozoal drugs such as Amphotericin B intravenously in very high doses, however it is many times too late and most of the time the infection results in death.[2] Recently, however, the drug Miltefosine showed promising results as an amoebicidal drug and was listed by the CDC as an emergency treatment drug that can be ordered if any patient is diagnosed with PAM recommending a dose of a 50mg capsule taken 3 times a day.[1] In July of 2013 this drug was used with success to treat Kali Hardig, a 12 year old girl from Arkansas after she contracted the disease at a waterpark. Doctors administered this drug to Hardig intravenously after having lowered her body temperature to 93 degrees and Hardig made a recovery after 55 days.
TARGET INFORMATION:
The target of this drug is still under investigation but it is strongly suggested that the target is a protein called nfa1 that is a key protein in the amoeba’s locomotion, adherence, and phagocytic abilities. This protein is found in the pseudopods of N. Fowleri and without it the amoeba would not be capable of moving by using its pseudopods and it is not capable of ingesting food by using food cups to ingest using phagocytosis. Naegleria gruberi is a non-pathogenic species of Naegleria and in a study done in 2006 the nfa1 protein was expressed in transinfected N. gruberi through the method of promoter modification. This resulted in the transinfected N. gruberi becoming pathogenic which supports the conclusion that the nfa1 gene is a key protein in making the N. fowleri amoeba pathogenic and capable of adhering to a human’s olfactory nerves.[3] The nfa1 protein is 13.1 kDa in size and if this protein is inhibited then the amoeba cannot spread as it usually does and will fail to be pathogenic.
DRUG INFORMATION:
The drug miltefosine, also known under the name Impavido or Miltex, was originally derived artificially from a group of chemical compounds called alkylphosphocholines which are artificially synthesized phospholipid-like molecules. Miltefosine was originally being investigated as a potential cancer drug but it resulted in being toxic at the levels needed for effective treatment. It then was rediscovered as an anti-fungal and anti-protozoal drug and it is currently patented as a drug to treat leishmaniasis and atopic dermatitis. It is used in emergencies for PAM but since PAM is rare and has a very poor prognosis there have not been any clinical trials done of this drug.
Figure 3. A schematic representation of miltefosine, a non-polar phospholipid-like drug
Formula: C21H46NO4P
Molecular weight: 407.568002 g/mol
CAS Number: 58066-85-6
The next step in the development of miltefosine or another similar drug alternative treatment for PAM would be to gain a better understanding of how miltefosine binds to the nfa1 protein inhibiting it and causing the spread of infection to stop. There have been several in vitro tests done using miltefosine on living N. fowleri to observe the drug’s beneficial effects and there have been tests done in vivo on mice to determine what concentrations are most effective which is great information but it would still be very beneficial to learn exactly how the drug binds to the protein in question. With this information, you can find other drugs, possibly drugs that are similar in structure to that of miltefosine, that make a better fit in the protein or do a better job of inhibiting the growth and spread of that particular protein. Having a better understanding of the binding of the drug to the protein will also help determine if there are certain conditions where binding is improved and the drug is more effective, maybe it binds more effectively when the patient has a lower body temperature such as when Hardig’s treatment proved effective in the summer of 2013. The fact that this disease occurs very rarely has a significant impact on how much research is done on the development of an effective drug such as miltefosine. Not only do the relatively few cases and fast progression of the disease make it very difficult to study the effects of a certain drug treatment but this also causes the funds for any research to be almost nonexistent. Despite these facts it is still important to find a drug such as miltefosine that can treat this disease if caught early since there are on average 2-3 cases every summer, all of which are most likely fatal.
REFERENCES:
[1] CDC, Naegleria fowleri - Primary Amebic Meningoencephalitis (PAM). Centers for Disease Control and Prevention 2014 http://www.cdc.gov/parasites/naegleria/
[2] Jong-Hyun Kim, Suk-Yul Jung, Effect of Therapeutic Chemical Agents In Vitro and on Experimental Meningoencephalitis Due to Naegleria fowleri. Antimicrob Agents Chemother 2008, 52, (11), 4010–4016.
[3] Song KJ, Jeong SR, Naegleria fowleri: functional expression of the Nfa1 protein in transfected Naegleria gruberi by promoter modification. Exp Parasitol 2006, 112, (2), 115-20.